Quillaja saponins are potent vaccine adjuvants but suffer from a number of drawbacks, including aqueous instability and toxic side effects. Structure- activity studies suggest that Schiff-base formation between the aglycon aldehyde of saponins and T-lymphocytes is essential to their adjuvant activity, but that structural features contributing to their toxicity and instability are not. Preliminary evaluations at Ribi ImmunoChem with an open-chain analog of the aldehydic aglycon of Quillaja saponins show that this novel amphiphathic aldehyde stimulates both antibody and T-cell responses in mice-presumably via Schiff-base activation of lymphocytes. We propose to further this initial discovery by investigating the adjuvant activity of simple hydrophilic and lipophilic derivatives of this amphipathic aldehyde which contain additional structural features of saponins important to adjuvanticity but lack those associated with toxicity and instability. Our aim is to identify a potent yet safe mechanism-based vaccine adjuvant for further molecular modification and/or clinical development. The proposed synthetic mimetics of saponin adjuvant will be prepared from readily available starting materials and evaluated in murine models for their ability to augment antigen-specific humoral and cell-mediated immune responses to hepatitis B and influenza antigens. Serum and mucosal immune responses to both intranasal and subcutaneous vaccination will be assessed. PROPOSED COMMERCIAL APPLICATIONS: This new class of synthetic adjuvants can potentially improve the safety and efficacy of both existing infectious disease vaccines and emerging synthetic vaccines. The anticipated high aqueous solubility and stability of these adjuvants should also facilitate vaccine formulation and administration.